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Background: Patients with peripheral artery disease (PAD) are at increased risk for major adverse limb and cardiac events including mortality. Developing screening tools capable of accurate PAD identification is a necessary first step for strategies of adverse outcome prevention. This study aimed to determine whether machine analysis of a resting Doppler waveform using deep neural networks can accurately identify patients with PAD. Methods: Consecutive patients (4/8/2015 – 12/31/2020) undergoing rest and postexercise ankle–brachial index (ABI) testing were included. Patients were randomly allocated to training, validation, and testing subsets (70%/15%/15%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict normal (> 0.9) or PAD (⩽ 0.9) using rest and postexercise ABI. A separate dataset of 151 patients who underwent testing during a period after the model had been created and validated (1/1/2021 – 3/31/2021) was used for secondary validation. Area under the receiver operating characteristic curves (AUC) were constructed to evaluate test performance. Results: Among 11,748 total patients, 3432 patients met study criteria: 1941 with PAD (mean age 69 ± 12 years) and 1491 without PAD (64 ± 14 years). The predictive model with highest performance identified PAD with an AUC 0.94 (CI = 0.92–0.96), sensitivity 0.83, specificity 0.88, accuracy 0.85, and positive predictive value (PPV) 0.90. Results were similar for the validation dataset: AUC 0.94 (CI = 0.91–0.98), sensitivity 0.91, specificity 0.85, accuracy 0.89, and PPV 0.89 (postexercise ABI comparison). Conclusion: An artificial intelligence-enabled analysis of a resting Doppler arterial waveform permits identification of PAD at a clinically relevant performance level.

Clinical differentiation of buttock claudication from pseudo-claudication (neuromuscular etiology) is often challenging and cannot be diagnosed non-invasively using standard ankle-brachial index (ABI) with exercise. The aim of this study was to evaluate the reliability of exercise transcutaneous oximetry (ExTcPO2) to accurately detect significant internal iliac artery (IIA) inflow stenosis. Methods: Data from a prospectively maintained registry of consecutive patients undergoing ExTcPO2 for evaluation of buttock and hip exertional discomfort as well as arterial imaging within 12 months were retrospectively analyzed. ExTcPO2 was performed on a treadmill (10% slope; 2 mph speed); measured at buttocks, upper back and calf (rest, with exercise) to document the baseline normal, degree of change with exercise and recovery patterns. A Delta from Resting Oxygen Pressure (DROP) (buttock- back TcPO2 mmHg) ≥15 mm Hg was considered significant. A blinded physician performed aorto-iliac arterial stenosis quantification and receiver operating characteristic (ROC) curve analysis was used to determine sensitivity and specificity to diagnose severe inflow reduction (≥70%) based upon a diagnostic DROP ≥15 mm Hg. Results: One hundred and eleven patients (M:F::79:32, mean age 70, range 18-90 years) with available concomitant imaging (CTA 90, DUS 21) were included in the study. Indications for testing were suspected vascular (82), or neuromuscular (29) symptoms. ExTcPO2 study confirmed the clinical suspicion of the state of IAA inflow in 81% (91/111) of patients. DROP ≥15 mm Hg had a sensitivity, specificity, PPV, NPV of 56, 80, 70, and 68% respectively for prediction of severe IIA inflow reduction (p value

Objective To evaluate the relationship between peripheral arterial disease (PAD) and incident atrial fibrillation (AF) and its clinical and pathophysiologic implications on ischemic stroke and all-cause mortality. Patients and Methods We identified all adult patients in the Mayo Clinic Health System without a previous diagnosis of AF undergoing ankle-brachial index (ABI) testing for any indication from January 1, 1996, to June 30, 2018. Retrospective extraction of ABI data and baseline echocardiographic data was performed. The primary outcome of interest was incident AF. The secondary outcomes of interest were incident ischemic stroke and all-cause mortality. Results A total of 33,734 patients were included in the study. After adjusting for demographic and comorbidity variables, compared with patients who had normal ABI (1.0 to 1.39), there was an increased risk of incident AF in patients with low ABI ( Conclusion In this large cohort of ambulatory patients undergoing ABI measurement, patients with PAD were at increased risk for incident AF, ischemic stroke, and mortality. In these high-risk patients with abnormal ABI, particularly severe PAD and cardiac structural abnormalities, routine monitoring for AF and management of cardiovascular risk factors may be warranted.

The calf muscle pump is a major determinate of venous return in the legs but has not been studied as a risk factor for venous thromboembolism (VTE). A population-based cohort study of Olmsted County, Minnesota residents was performed using calf pump function (CPF) measurements from venous plethysmography studies from 1998 to 2015. Patients with a history of VTE were excluded. Nursing validated VTE outcomes from the Rochester Epidemiology Project were identified after the index study date, and patients with reduced CPF (rCPF) were compared with patients with normal CPF. A total of 1532 patients with recorded CPF (28% air and 72% strain gauge plethysmography) were included; 591 (38.5%) had normal CPF, 353 (23.0%) had unilateral rCPF, and 588 (38.3%) had bilateral rCPF. Any VTE occurred in 87 patients (5.7%) after a median follow-up of 11.7 years (range, 0-22.0 years). Comparing patients with bilateral reduced to bilateral normal CPF, the unadjusted hazard ratio (HR) for incident VTE was 2.0 (95% confidence interval [CI], 1.2-3.4) and after adjusting for age, BMI, and Charlson Comorbidity Index, the HR was 1.68 (95% CI, 0.98-2.89). The adjusted HR for ipsilateral deep vein thrombosis was evaluated in 3064 legs comparing legs with reduced to normal CPF and was 1.71 (95% CI, 1.03-2.84). Mortality was significantly higher in both the bilateral (P < .001) and unilateral (P < .001) rCPF groups compared with normal CPF. Our results demonstrate that CPF is a risk factor for VTE in an otherwise low-risk ambulatory population and might be a useful component in risk stratification models.

Objective To evaluate usability of a quality improvement tool that promotes guideline-based care for patients with peripheral arterial disease (PAD). Patients and Methods The study was conducted from July 19, 2018, to August 21, 2019. We compared the usability of a PAD cohort knowledge solution (CKS) with standard management supported by an electronic health record (EHR). Two scenarios were developed for usability evaluation; the first for the PAD-CKS while the second evaluated standard EHR workflow. Providers were asked to provide opinions about the PAD-CKS tool and to generate a System Usability Scale (SUS) score. Metrics analyzed included time required, number of mouse clicks, and number of keystrokes. Results Usability evaluations were completed by 11 providers. SUS for the PAD-CKS was excellent at 89.6. Time required to complete 21 tasks in the CKS was 4 minutes compared with 12 minutes for standard EHR workflow (median, P = .002). Completion of CKS tasks required 34 clicks compared with 148 clicks for the EHR (median, P = .002). Keystrokes for CKS task completion was 8 compared with 72 for EHR (median, P = .004). Providers indicated that overall they found the tool easy to use and the PAD mortality risk score useful. Conclusions Usability evaluation of the PAD-CKS tool demonstrated time savings, a high SUS score, and a reduction of mouse clicks and keystrokes for task completion compared to standard workflow using the EHR. Provider feedback regarding the strengths and weaknesses also created opportunities for iterative improvement of the PAD-CKS tool.

International audience; This expert consensus statement on the interpretation of peripheral arterial and venous spectral Doppler waveforms was jointly commissioned by the Society for Vascular Medicine (SVM) and the Society for Vascular Ultrasound (SVU). The consensus statement proposes a standardized nomenclature for arterial and venous spectral Doppler waveforms using a framework of key major descriptors and additional modifier terms. These key major descriptors and additional modifier terms are presented alongside representative Doppler waveforms, and nomenclature tables provide context by listing previous alternate terms to be replaced by the new major descriptors and modifiers. Finally, the document reviews Doppler waveform alterations with physiologic changes and disease states, provides optimization techniques for waveform acquisition and display, and provides practical guidance for incorporating the proposed nomenclature into the final interpretation report.

Fenestrated-branched endovascular repair of thoracoabdominal aneurysms carries a risk of spinal cord ischemia owing to extensive coverage of intercostal arteries, but other consequences of decreased flow to the paraspinal muscles have not been delineated. We describe a 54-year-old woman treated by multibranched thoracoabdominal aneurysm repair who developed severe disabling exertional thoracic and lumbar back pain after the operation. Despite physical therapy, the patient remains with disabling symptoms at 2 years of follow-up. Transcutaneous oxygen pressures confirmed exercise-induced decrease in oxygen pressure, consistent with decreased muscle perfusion. We propose the term paraspinal muscle claudication to describe these symptoms.

Introduction: Patients with concomitant peripheral artery disease (PAD) and heart failure (HF) are known to have increased morbidity and mortality. Though they share common risk factors, the utility of HF screening in patients with PAD remains controversial and without international consensus. We sought to clarify whether PAD is an independent risk factor for HF. Methods: We performed a retrospective analysis of adult patients without a history of heart failure who underwent ankle brachial index (ABI) measurement for any indication between 1995-2020. Patients were then stratified by ABI: PAD with low ABI (1.39). The associations between PAD and incident diagnosis of heart failure, systolic dysfunction (HF with reduced ejection fraction, HFrEF), and diastolic dysfunction (HF with preserved ejection fraction, HFpEF) were assessed. All patient and outcomes variables were obtained using the institutional electronic health record. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, hypertension, diabetes, and active tobacco use. Results: The cohort included 36,816 patients (median follow-up 4.21 years), of whom 2,116 (5.7%) were diagnosed with HF. Among HF patients, 1,110 (3.0%) had HFrEF and 1,006 (2.7%) had HFpEF. Both low and elevated ABI groups were associated with an increased risk of HF, both HFrEF, and HFpEF. After multivariable analysis, PAD with elevated ABI was associated with higher overall HF risk (HR, 2.36 [95% CI, 2.03, 2.73]) than low ABI (HR, 1.56 [95% CI, 1.40, 1.74]) when compared to normal ABI. Similarly, PAD with elevated ABI was associated with greater risk of HFrEF (HR, 2.37 [95% CI, 1.93, 2.92]) and HFpEF (HR, 1.82 [95% CI, 1.48, 2.25]) than PAD with low ABI (HFrEF: HR 1.77 [95% CI, 1.52, 2.07], HFpEF: HR 1.31 [95% CI, 1.12, 1.52]). Conclusions: PAD, especially with elevated ABI, is an independent risk factor for heart failure even after adjusting for common HF risk factors. Our findings support HF screening in PAD patients, but longitudinal data on HF morbidity and mortality is necessary to evaluate the value of this practice.

Introduction: Peripheral arterial disease (PAD) increases cardiovascular (CV) morbidity and mortality, but remains underdiagnosed and undertreated. Several trials support low-dose rivaroxaban in PAD treatment, although this has yet to be widely adopted in clinical practice. The effect of warfarin and direct oral anticoagulants (DOACs) on comprehensive PAD outcomes warrants further study. Hypothesis: Anticoagulant therapy, particularly DOACs, improves CV outcomes in PAD. Methods: We conducted a retrospective study of patients who underwent ankle-brachial index testing (ABI) from 1996 – 2020 at Mayo Clinic. We included patients with PAD defined by abnormal ABI (/=1.4). Prolonged (>6 months) DOAC or warfarin use was compared to no anticoagulant therapy. Multivariable (MV) regression, controlling for baseline CV risk factors, was used. Results: 21,891 patients had abnormal ABI readings; 3,093 were on warfarin and 267 were on DOAC for any indication. Anticoagulation improved mortality, with DOACs superior to warfarin. DOACs improved critical limb ischemia (CLI)/amputation in univariate analysis, although this was not significant in MV. Patients with poorly compressible vessels (ABI >/=1.4) had increased limb outcomes compared to reduced ABI ( Conclusion: Anticoagulant therapy improved mortality in a large cohort of PAD patients. The risk of limb events appears improved in those on DOACs. DOACs showed improved risk profiles compared to warfarin regarding CV and bleeding outcomes.

OBJECTIVE. The purpose of this study is to report the frequency of major bleeding after percutaneous image-guided core biopsy and its association with aspirin usage and duration of prebiopsy aspiri...

Context Peripheral artery disease (PAD) is highly prevalent in the general population, affecting up to 25% of patients 55 years of age or older. There is a known association with acute ischemic stroke, but limited large cohort studies exist pertaining to the relationship between PAD severity and incident ischemic stroke. Objectives To evaluate the risk of incident ischemic stroke and mortality along the spectrum of low and elevated ankle brachial index (ABI) measurement. Methods We performed a retrospective extraction of ABI data of all adult patients who underwent lower extremity physiology study for any indication from January 1, 1996 to June 30, 2018 in the Mayo Clinic health system. PAD was categorized into severe, moderate, mild, and borderline based on ABI measurements and poorly compressible arteries (PCA). These were compared with normal ABI measurements. Associations of PAD/PCA with new ischemic stroke events and all cause mortality were analyzed. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. Results A total of 39,834 unique patients were included with a median follow up duration of 4.59 years. All abnormal ABI groups, except borderline PAD, were associated with increased risk of incident ischemic stroke after multivariate regression compared to normal ABI. A severity-dependent association was observed between PAD and ischemic stroke with moderate (HR, 1.22 [95% CI, 1.10–1.35]) and severe (HR, 1.19 [95% CI, 1.02–1.40]) categories conferring similar risk in comparison to normal ABI. Patients with PCA carried the greatest ischemic stroke risk (HR, 1.30 [95% CI, 1.15–1.46]). Similarly, abnormal ABI groups were associated with a significant risk for all cause mortality in a severity-dependent manner, with severe PAD conferring the greatest risk (HR, 3.07 [95% CI, 2.88–3.27]). Conclusions This study adds to the growing body of evidence that both PAD and PCA are independent risk factors for incident ischemic stroke and all cause mortality. The association of PAD severity and PCA with risk of ischemic stroke may help clinicians with risk stratification and determining treatment intensity.

Introduction Given the potential side effects and the lack of data on its efficacy, the role of statins in the very elderly (age 75+) with peripheral arterial disease (PAD) is uncertain. Previous studies have shown significant mortality benefit in very elderly patients with coronary artery disease, but the effect in PAD has not been evaluated. Methods Very elderly patients aged 75 to 80 with at least five years of follow-up who underwent ankle-brachial index (ABI) measurement were included. PAD was defined as either low ABI 1.40. Demographic, medication use, comorbidity and mortality data was obtained using the electronic medical record. Univariate and multivariate Cox proportional hazard analyses were performed. Results In total, 4,560 very elderly subjects with PAD were included in the analysis. The median age was 77 (interquartile range 76–79) and 39% were female. 3,462 (76%) had low ABI while 1098 (24%) had high ABI. Univariate analysis showed that patients on statins were more likely to be male, have diabetes, have coronary artery disease, and have hyperlipidemia. Overall, 1,355 (30%) patients died in the five-year period. Unadjusted all-cause mortality hazard ratios for patients with low or high ABI with statin use was 0.66 (95% confidence interval [CI]: 0.57–0.75) and 0.80 (95% CI: 0.66–0.97), respectively. After adjusting for age, sex, coronary artery disease and diabetes, statin use in low and high ABI was still associated with significant reductions in risk of all-cause mortality of 0.59 (95% CI: 0.51–0.67) and 0.66 (95% CI: 0.54–0.80), respectively. The survival curve for very elderly patients with PAD by statin use is shown in Figure 1. Conclusion Statin use in the very elderly was associated with lower risk of all-cause mortality in the five-year period after diagnosis of PAD. There appears to be a mortality benefit with statin use in the very elderly with PAD, though careful consideration of benefits and side effects should be individualized in this age group. Figure 1 Funding Acknowledgement Type of funding source: None

Introduction Antiplatelet therapy is the cornerstone of treatment for many atherosclerotic vascular pathologies including peripheral arterial disease (PAD). Patients with PAD often have comorbid conditions that require complex antithrombotic therapy, i.e. combined antiplatelet and anticoagulation. Methods All adult patients undergoing ankle brachial index (ABI) measurements were included in the study. ABI values between 1.00 and 1.40 were considered normal, and values below 1.00 or above 1.40 were considered PAD. Demographic, comorbidity and outcome data were obtained using diagnostic codes from the electronic health record. Three medication classes were analyzed: aspirin, non-aspirin oral antiplatelets (e.g. P2Y12 inhibitors) and oral anticoagulants (warfarin and the direct oral anticoagulants). Medication use was determined for patients who had been on a medication for at least one year. Cox proportional hazard analysis for the time to first bleeding event was analyzed. Bleeding was defined as any bleeding requiring medical evaluation (including clinically-relevant non-major bleeding and major bleeding). Results In all, 40,144 patients were included in the analysis (mean age 66±15, 43% female). Patients with PAD were more likely to be on double therapy (one antiplatelet with anticoagulation) (28% vs 19%) and triple therapy (dual antiplatelet with anticoagulation) (10% vs 4%). Unadjusted hazard ratios for bleeding risk showed increased risk of bleeding for patients with PAD (1.18, 95% confidence interval [CI]: 1.08–1.29), though the association is no longer present after adjustment for antithrombotic therapy. Adjusting for age, sex and PAD class, compared to no antithrombotic therapy, there was increased risk of bleeding for monotherapy (1.91, 95% CI: 1.61–2.26), double therapy (3.40, 95% CI: 2.89–4.00) and triple therapy (5.00, 95% CI: 4.21–5.96). Among medications, aspirin and anticoagulant use was independently associated with the greatest increase in risk of bleeding. Conclusion Patients in PAD are at increased risk of bleeding secondary to antithrombotic therapy. Complex antithrombotic therapy with double or triple therapy confer additional bleeding risk, particularly regimens containing aspirin and oral anticoagulants. Funding Acknowledgement Type of funding source: None

Calf muscle pump (CMP) promotes venous return from the lower extremity and contributes to preload and cardiac output. Impaired CMP function may reflect a measure of frailty or cumulative disease burden or may impede cardiac function. The study objective was to test the hypothesis that impaired CMP negatively impacts survival. Consecutive adult patients who underwent venous strain gauge plethysmography at the Mayo Clinic Gonda Vascular Laboratory (January 1, 1998 – December 31, 2011) were assessed for overall survival. Patients with venous incompetence, venous obstruction or unilateral calf pump dysfunction were excluded. Risk of mortality was assessed with Cox proportional hazard ratios and after adjusting for Charlson Comorbidity Index variables. Over the study period, 2728 patients were included in the analysis. Compared to patients with normal CMP, those with impaired CMP were older ( p < 0.001), predominantly female ( p = 0.01) and had higher mean Charlson scores ( p < 0.001). Patients with impaired CMP had a higher mortality rate at 5 (8.9% vs 2.4%), 10 (17.5% vs 5.9%), and 15 years (22.8% vs 8.3%) compared to those with normal CMP ( p < 0.001 for each comparison). Of patients with heart failure, those with impaired CMP had worse survival at each 5-year increment compared to those with normal CMP ( p < 0.05 at each increment). In conclusion, impaired CMP appears to be an independent predictor of poor outcomes after adjusting for variables within the Charlson Comorbidity Index. The association between impaired CMP, heart failure, and mortality may represent a negative impact on circulatory function or a surrogate measure of frailty.

Context Reduced bone material strength index (BMSi) and increased cortical porosity (CtPo) have emerged as potentially contributing to fracture risk in type 2 diabetes mellitus (T2DM) patients. Objective To determine whether BMSi or CtPo are related to other diabetic complications. Design Cross-sectional observational study. Setting Subjects recruited from a random sample of southeast Minnesota residents. Participants A total of 171 T2DM patients (mean age, 68.8 years) and 108 age-matched nondiabetic controls (mean age, 67.3 years). Main Measures Bone material strength index was measured using microindentation, skin advanced glycation end-products (AGEs) measured using autofluorescence, high-resolution peripheral quantitative computed tomography at the distal radius and tibia, assessment of diabetic microvascular complications including urine microalbuminuria, retinopathy, neuropathy, and vascular disease (ankle brachial index and transcutaneous oxygen tension [TcPO2]). All analyses were adjusted for age, sex, and body mass index. Results Skin AGEs were negatively correlated with the BMSi in both T2DM (r = -0.30, P < 0.001) and control (r = -0.23, P = 0.020) subjects. In relating diabetic complications to CtPo, we found that T2DM patients with clinically significant peripheral vascular disease (TcPO2 ≤ 40 mm Hg) had higher (+21.0%, P = 0.031) CtPo at the distal tibia as compared to controls; in these subjects, CtPo was negatively correlated with TcPO2 at both the distal tibia (r = -0.39, P = 0.041) and radius (r = -0.41, P = 0.029). Conclusions Our findings demonstrate that bone material properties are related to AGE accumulation regardless of diabetes status, while CtPo in T2DM patients is linked to TcPO2, a measure of microvascular blood flow.

Background Ankle‐brachial indexes ( ABI ) are a noninvasive diagnostic tool for peripheral arterial disease and a marker of increased cardiovascular risk. ABI is calculated using the highest systolic blood pressure of the 4 ankle arteries (bilateral dorsalis pedis and posterior tibial). Accordingly, patients may be assigned a normal ABI when the result would be abnormal if calculated using one of the other blood pressure readings. Cardiovascular outcomes for patients with discordant ABI s are undescribed. Methods and Results We performed a retrospective study of patients who underwent ABI measurement for any indication between January 1996 and June 2018. Those with normal ABI s (1.00–1.39) were included. We compared patients with all 4 normal ABI s (calculated using all 4 ankle arteries; n=15 577, median age 64.0 years, 54.4% men) to those with discordant ABI s (at least 1 abnormal ABI ≤0.99; n=2095, median age 66.0 years, 47.8% men). The outcomes assessed were ischemic stroke, myocardial infarction, and all‐cause mortality. Compared with patients with concordant normal ABI s, patients with discordant ABI s were older; women; smoked; and had chronic kidney disease, coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease, hypertension, or prior stroke. Patients with discordant ABI s had a greater risk of myocardial infarction (hazard ratio [HR], 1.31; 95% CI, 1.10–1.56), ischemic stroke ( HR, 1.53; 95% CI, 1.37–1.72), and all‐cause mortality ( HR, 1.27; 95% CI, 1.16–1.39), including after adjustment for baseline comorbidities. Conclusions Discordant ABI results were associated with an increased risk of myocardial infarction, stroke, and all‐cause mortality in the studied population. Clinicians should examine ABI calculations using all 4 ankle arteries to better characterize a patient's cardiovascular risk.

Patients with Type 2 Diabetes (T2D) are at higher fracture risk despite having relatively normal or even increased BMD by DXA. Increased cortical porosity has emerged as a potential factor contributing to fragility fractures in T2D. However, there is conflicting evidence whether T2D patients have increased cortical porosity. We hypothesized that microvascular complications have an important role in cortical porosity. Thus, we performed high-resolution peripheral quantitative computed tomography imaging at the distal radius and tibia to evaluate bone microarchitecture in men with T2DM age ≥ 50 yrs or postmenopausal women with T2DM and nondiabetic controls. Comprehensive diabetic complications were assessed in all patients including urine microalbuminuria, retinopathy, neuropathy (touch, temperature, and vibration sensation), ankle brachial index (ABI) and transcutaneous oxygen tension (TcPO2). Percent differences between groups were obtained from linear regression models adjusting for age, BMI, and sex. Relationships between variables were assessed using adjusted Spearman correlations. A total of 164 T2D patients (mean age 68.9 ±7.8 yrs.; 56.7% men; HbA1C=7.7 ±0.9%; mean diabetes duration 15.2 yrs.) and 107 nondiabetic controls (mean age 67.3±8.8 yrs.; 42.1% men; HbA1C =5.4 ±0.3%) were recruited to the study. Overall, there was a trend for increased cortical porosity at the distal tibia in the T2D group (+12.2%; p=0.063) compared with nondiabetic controls. Of note, TcPO2 was negatively correlated with cortical porosity at the distal radius (r= -0.17; p= 0.039) and distal tibia (r= -0.15; p= 0.073). In particular, the Low TcPO2 (≤40 mmHg) group (n=29) had greater cortical porosity at the distal tibia (+19.6 %; p=0.037) compared with the High TcPO2 (>40 mmHg) group (n=133). In addition, the low TcPO2 group had a significant increase in cortical porosity in the distal tibia (+24.8% p=0.020) compared with nondiabetic controls. In conclusion, this is the first evidence in humans indicating that TcPO2, a measure of microvascular blood flow, is linked to cortical porosity in the distal radius and tibia in T2D patients. Our findings may explain the conflicting findings regarding cortical porosity in T2D because only T2D patients with impaired microvascular blood flow have increased cortical porosity. Collectively, our data indicate that cortical porosity is a microvascular complication of longstanding T2D.

International audience; Exertional lower limb pain is a frequent diagnostic issue in elderly patients. Arterial claudication results from the mismatch between the oxygen requirement of, and oxygen delivery to the exercising muscles. Non-invasive vascular investigations (ultrasound imaging, plethysmography or segmental pressure) are used in routine at rest or following exercise, but none can be used during walking or to directly monitor cutaneous oxygen delivery to the limb. Here, we review the methods, tips and traps of the transcutaneous oxygen pressure measurement technique and potential applications.Transcutaneous oxygen pressure measurement is largely used in vascular medicine for patients with critical limb ischemia. It can also detect regional blood flow impairment at the proximal and distal limb simultaneously and bilaterally during exercise. Exercise-oximetry can also analyze systemic oxygen pressure changes on a reference area on the chest, to screen for occult pulmonary disease. As a surface technique, it does not directly measure muscle oxygen content but provides a reliable estimation of regional blood flow impairment.With the use of a recently reported index that is independent of the unknown transcutaneous gradient for oxygen, exercise-oximetry provides some accurate information compared to classical non-invasive vascular investigations to argue for a vascular or non-vascular origin of exertional lower limb pain during exercise. Although a time consuming technique, it is a simple test and it is progressively spreading among referral vascular centers as a useful non-invasive diagnostic tool for patients suspected of arterial claudication.

Patients with end-stage renal disease undergoing kidney transplant often have diffuse atherosclerosis and high cardiovascular morbidity and mortality rates. We analyzed the correlation of peripheral arterial disease (PAD), here quantified by an abnormal ankle–brachial index (ABI) measured within the 5 years prior to kidney transplant, with graft failure and mortality rates (primary end points) after adjusting for known cardiovascular risk factors (age, sex, smoking history, hypertension, diabetes, stroke, known coronary artery disease or heart failure, years of dialysis). Of 1055 patients in our transplant population, 819 had arterial studies within the 5 years prior to transplant. Secondary end points included myocardial infarction; cerebrovascular accident; and limb ischemia, gangrene, or amputation. Low ABI was an independent and significant predictor of organ failure (OR, 2.77 (95% CI, 1.68–4.58), p

Peri-procedural anticoagulant management hinges on the balance of hemorrhagic and thrombotic complications. The radiologist is tasked with accurately assessing the hemorrhagic risk for patients undergoing procedures, taking into account procedural bleeding rates, underlying coagulopathy based on lab tests, and use of anticoagulants. The purpose of this article is to provide a contemporary review of commonly used anticoagulants and, incorporating published evidence, review their management related to image-guided procedures.

Purpose To report incidence of bleeding after image-guided percutaneous core needle biopsy performed in patients taking clopidogrel within 5 days. Materials and Methods This was a retrospective review of image-guided percutaneous core needle biopsies performed in patients with clopidogrel use within 5 days of the procedure between January 2002 and November 2014. Data including biopsy site, needle size, number of samples, and serum coagulation studies were collected. Routine follow-up of patients was performed 24–72 hours after biopsy. Major bleeding complications were defined as grade 3 or greater using Common Terminology Criteria for Adverse Events. There were 63 deep biopsies performed in 63 patients with recent use of clopidogrel. Mean time of clopidogrel abstinence before biopsy was 2.9 days ± 1.9 (median 3 days). Clopidogrel had been taken within 24 hours of the biopsy by 12 patients. There were 48 patients (76%) who also took aspirin within 5 days of the procedure. The most common procedure was liver biopsy (21/63; 33%), followed by lung (12/63; 19%), abdominal/pelvic/retroperitoneal mass (12/63; 19%), and renal (11/63; 17%) biopsies. Results A major bleeding complication (1/63; 1.6%) occurred after injury to an intercostal artery during lung biopsy, which was successfully treated with coil embolization. No minor bleeding complications were identified. Conclusions In this study comprising a small number of patients undergoing various biopsy procedures, recent clopidogrel use was associated with a very low incidence of major bleeding.

Introduction Lower extremity physiologic studies are an important non-invasive diagnostic tool in peripheral arterial disease (PAD). PAD and atrial fibrillation (AF) are associated with increased cardiovascular and all-cause mortality. Purpose To evaluate the association between PAD and new-onset AF and the risk of stroke. Methods We performed a study of all patients without AF undergoing ankle-brachial index (ABI) for any indication between January 1996 to June 2018. The ABI cut-off were as follows: abnormal ABI (0–0.99), normal ABI (1.00–1.39) and poor vessel compressibility (PC) (1.40+). Demographic, comorbidity, and outcome variables were extracted using the electronic medical record. Results Overall, 34,441 patients (mean age 66.8±14.3, 57.3% male, 88.2% white) were included in the study with a median follow-up of 7.2 years (interquartile range, 3.0–12.9 years). Multivariate Cox proportional hazard analysis showed increased risk of new-onset AF for male sex, older age, hypertension, coronary artery disease, cerebrovascular disease, chronic kidney disease stage III or greater, congestive heart failure, chronic obstructive pulmonary disease, and cancer (all p Conclusion Abnormalities in ABI results, particularly poorly-compressible vessels, are independently associated with new-onset atrial fibrillation in a large ambulatory cohort. While the mechanism cannot be assessed, common inflammatory mechanisms and increased vascular stiffness may play an important role. Identification of AF in these at-risk patients may improve cardiovascular outcomes.

Background Peripheral arterial disease is a marker of aggressive atherosclerosis. The ankle brachial index (ABI) is a simple and non-invasive tool to diagnose peripheral arterial disease (PAD). Patients with PAD are at increased risk for ischemic strokes and other cardiovascular diseases. Purpose To evaluate the association of abnormal ABI and poorly compressible vessels with ischemic stroke in a large patient cohort. Methods We analyzed lower extremity vascular studies of all patients with ABI measurements at a tertiary care hospital between January 1996 and August 2018. PAD is defined as ABI1.4 while ABI between 1.0–1.4 is normal. Association of these ABIs with new ischemic stroke events post ABI measurement were analyzed after adjusting for high risk confounders such as atrial fibrillation. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. Results In total, 38,016 unique patients (mean age 66.1±14.8 years, female 42.3%) were included. Abnormal ABI was found to be more prevalent among elderly male patients compared to patients with normal ABI. In contrast to non-PAD patients, both PAD and PC/NC patients as defined by ABI had a statistically significant risk of ischemic stroke, with PAD conferring the greatest risk compared to PC/NC vessels. The data is summarized in Table 1. Table 1 Unadjusted HR p-value Adjusted HR p-value PAD vs. No PAD 2.77 (2.62, 2.92) Conclusion This study adds to the growing body of evidence that PAD and poorly-compressible vessels are independently associated with an increased risk of ischemic stroke. Given the associated risk of cerebrovascular disease, clinicians should aggressively treat to minimize risk factors in those with abnormal ABIs.

Heart Failure (HF) and Peripheral Arterial Disease (PAD) share common risk factors, such as diabetes and smoking. PAD is an independent predictor of mortality in patients with HF. There is regional variability in the recommendation for screening patients with PAD for HF. We examined the incidence of

Background Automated individualized risk prediction tools linked to electronic health records (EHRs) are not available for management of patients with peripheral arterial disease. The goal of this study was to create a prognostic tool for patients with peripheral arterial disease using data elements automatically extracted from an EHR to enable real‐time and individualized risk prediction at the point of care. Methods and Results A previously validated phenotyping algorithm was deployed to an EHR linked to the Rochester Epidemiology Project to identify peripheral arterial disease cases from Olmsted County, MN, for the years 1998 to 2011. The study cohort was composed of 1676 patients: 593 patients died over 5‐year follow‐up. The c‐statistic for survival in the overall data set was 0.76 (95% confidence interval [CI], 0.74–0.78), and the c‐statistic across 10 cross‐validation data sets was 0.75 (95% CI, 0.73–0.77). Stratification of cases demonstrated increasing mortality risk by subgroup (low: hazard ratio, 0.35 [95% CI, 0.21–0.58]; intermediate‐high: hazard ratio, 2.98 [95% CI, 2.37–3.74]; high: hazard ratio, 8.44 [95% CI, 6.66–10.70], all P, See Editorial by https://10.1161/JAHA.118.011184

Objective To quantify compliance with guideline recommendations for secondary prevention in peripheral artery disease (PAD) using natural language processing (NLP) tools deployed to an electronic health record (EHR) and investigate provider opinions regarding clinical decision support (CDS) to promote improved implementation of these strategies. Patients and Methods Natural language processing was used for automated identification of moderate to severe PAD cases from narrative clinical notes of an EHR of patients seen in consultation from May 13, 2015, to July 27, 2015. Guideline-recommended strategies assessed within 6 months of PAD diagnosis included therapy with statins, antiplatelet agents, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and smoking abstention. Subsequently, a provider survey was used to assess provider knowledge regarding PAD clinical practice guidelines, comfort in recommending secondary prevention strategies, and potential role for CDS. Results Among 73 moderate to severe PAD cases identified by NLP, only 12 (16%) were on 4 guideline-recommended strategies. A total of 207 of 760 (27%) providers responded to the survey; of these 141 (68%) were generalists and 66 (32%) were specialists. Although 183 providers (88%) managed patients with PAD, 51 (25%) indicated they were uncomfortable doing so; 138 providers (67%) favored the development of a CDS system tailored for their practice and 146 (71%) agreed that an automated EHR-derived mortality risk score calculator for patients with PAD would be helpful. Conclusion Natural language processing tools can identify cases from EHRs to support quality metric studies. Findings of this pilot study demonstrate gaps in application of guideline-recommended strategies for secondary risk prevention for patients with moderate to severe PAD. Providers strongly support the development of CDS systems tailored to assist them in providing evidence-based care to patients with PAD at the point of care.

Background: We evaluated the role of increased cardiac troponin T (cTnT), vascular, and cardiac diseases in predicting 5 and 10-year all-cause mortality after kidney transplantation. Methods: We reviewed a cohort of 764 kidney transplant recipients and analyzed pertinent cardiovascular risk factors at the time of transplant evaluation. Proportional hazards regression analysis with bootstrapping method was utilized to provide a risk stratification score for mortality. Results: Mean age was 58.8 years (SD 12.1) and median follow-up was 7.0 years (range 1 day to 18.0 years). Fifty-four percent of patients (n = 415) had cTnT measured (median 0.02 ng/mL, range 0.01–4.91). Fifty-three percent (n = 407) had vascular disease, 59% (n = 448) had diabetes, and 44% (n = 336) had cardiac disease pre-transplant. Sixty percent (n = 460) required dialysis. Older age, increased cTnT, pre-transplant vascular and cardiac diseases predicted mortality in multivariate analysis. We derived 2 scoring systems with and without cTnT – the ACV and ACTV scores (age, cardiac disease, elevated cTnT, and vascular disease) – as predictors of mortality after kidney transplant. Point assignments were: age 60–69 years (1), age ≥70 years (2), cardiac disease (1), cTnT ≥0.04 ng/mL (1), and vascular disease (1). Both scoring systems significantly predicted mortality. The ACTV score better delineated risk stratification across score levels (0–2, 3–4, and 5 points). Conclusions: We developed a risk schema predictive of all-cause mortality after kidney transplant in a derivation cohort. The ACTV score, including an elevated cTnT, provided superior prediction compared to a scoring system without cTnT. Further studies to validate these findings are needed.

Introduction: Peripheral arterial disease (PAD) is a strong predictor of systemic atherosclerosis with substantial morbidity and mortality. Medical management in PAD and coronary artery disease (CAD) has changed in recent eras with the use of high intensity statin and dual antiplatelet therapies. Hypothesis: Test whether mortality and major adverse cardiovascular events (MACE) (death and MI) has decreased over eras among PAD patients undergoning revascularization with percutaneous coronary intervention (PCI). Methods: Longitudinal cohort study of 549 patients who underwent PCI and non-invasive lower arterial study between 1997 and 2008 as identified in the Mayo Clinic PCI registry were stratified into 2 time eras: 1997-2003 (era1), and 2004-2008 (era2). PAD was assessed using the highest resting ABI and stratified according to established categories; < 0.90 (definite PAD); 1.00-1.39 (normal); and ≥ 1.40 defined a non-compressible artery. Kaplan-Meier methods were used to analyze follow-up survival. Results: Stratified by ABI over both time eras, 225 patients had PAD, 94 were non-compressible, and 142 were normal. Overall mortality rates were higher in era2 non-compressible and PAD patients than in non-PAD patients when compared to era1 (58%, 33%, 26%, vs 49% 32%, 19%, p Conclusions: Over the past two eras, the overall mortality has increased among patients with PAD and non-compressible vessels in era2 vs. era1 despite higher utilization of statin and antiplatelet therapies.

Background Lower extremity peripheral arterial disease (PAD) is a common medical condition causing substantial morbidity. Limited data exist on whether discrepancies in PAD prevalence exist between the lower extremities using resting ankle-brachial indices (ABIs) and postexercise pressures. Objective We predicted the prevalence of PAD between the lower extremities. Methods and Results Consecutive patients who had undergone a noninvasive arterial lower extremity study at Mayo Clinic, Rochester, MN, between January 1996 and December 2012 with suspected PAD were retrospectively reviewed. We identified 12,312 consecutive patients who underwent an arterial lower extremity and an exercise treadmill study. Prevalence of PAD was assessed at rest and after exercise using two criteria: a resting ABI ≤ 0.90 and a postexercise pressure decrease of > 30 mm Hg. Mean age was 67 ± 12 years and there were 4,780 (39%) women studied. At rest, we found a higher prevalence of PAD on the left extremity (27.4%) compared with the right (24.6%) (p Conclusion Using validated criteria of a resting ABI of ≤ 0.90 and postexercise ankle pressure decrease > 30 mm Hg, our results suggest that there is a significantly higher prevalence of PAD in the left lower extremity at rest, in contrast to a greater prevalence of abnormal postexercise testing in the right lower extremity. The reason(s) of these discrepancies remain to be studied.

Lower extremity physiologic testing also known as ankle-brachial indices (ABIs) are an important non-invasive diagnostic tool for peripheral arterial disease (PAD) and a risk marker for cardiovascular outcome. ABI is calculated by adapting the highest systolic blood pressure of the dorsalis pedis or

How best to approach a patient with peripheral arterial disease (PAD) can be an intimidating and confusing task. There are few disease processes as variable in location, presentation, and severity as those seen in the vasculopath. There are many etiologies to be considered simultaneously. Ironically, it is the variability of PAD that provides an opportunity to extract a comprehensive and tightly integrated history and physical examination that is nearly unparalleled in medicine. Similarly, there are few disease processes that offer the opportunity to impact so many aspects of the patient, literally from head to toe. This article, part of a series on PAD, focuses on the initial assessment and evaluation of the PAD, with pathophysiology, genetics, and treatment addressed in accompanying articles. Each patient with PAD is unique (Table 1). Even though the pathophysiology, risk factors, location, and eventual treatment options for a patient often prove routine, the manner in which the patient presents is anything but predictable.1 We have all had the experience of taking a well-structured history (Table 2) from a textbook patient, presented to an attending physician or a colleague, and then watched and listened in disbelief as the confirmatory history is nothing at all similar to what was heard 15 minutes earlier. Unfortunately, patients do not often read the textbook. As demonstrated by McDermott and colleagues,2 the discomfort caused by PAD is more often atypical than typical. Descriptions such as “tired,” “giving way,” “sore,” and “hurts” are offered more often than “cramp.” This forces the healthcare provider to meticulously clarify the location, quality, and circumstances of the discomfort. It is not unusual that a patient reports ≥2 types and locations of discomfort. Careful consideration for pain from both orthopedic and neurogenic sources must be taken. Each symptom should be individually addressed and clarified. These …

Key Points Question Are ankle-brachial indices associated with limb outcomes in community-dwelling patients with peripheral artery disease as identified by computational approaches applied to electronic health records? Findings In this cohort study of 1413 community-dwelling patients, peripheral artery disease was identified and limb outcomes were retrieved by computational approaches applied to electronic health records. Ankle-brachial indices of 1.4 or greater were associated with limb amputation and ankle-brachial indices less than 0.5 were associated with limb revascularization. Meaning Severe disease and poorly compressible arteries detected by ankle-brachial indices were associated with adverse outcomes in community-dwelling patients with peripheral artery disease; ascertainment of peripheral artery disease phenotypes and outcomes by computational approaches applied to electronic health records is feasible., Importance The prevalence and morbidity of peripheral artery disease (PAD) are high, with limb outcomes including revascularization and amputation. In community-dwelling patients with PAD, the role of noninvasive evaluation for risk assessment and rates of limb outcomes have not been established to date. Objective To evaluate whether ankle-brachial indices are associated with limb outcomes in community-dwelling patients with PAD. Design, Setting, and Participants A population-based, observational, test-based cohort study of patients was performed from January 1, 1998, to December 31, 2014. Data analysis was conducted from July 15 to December 15, 2017. Participants included a community-based cohort of 1413 patients with PAD from Olmsted County, Minnesota, identified by validated algorithms deployed to electronic health records. Automated algorithms identified limb outcomes used to build Cox proportional hazards regression models. Ankle-brachial indices and presence of poorly compressible arteries were electronically identified from digital data sets. Guideline-recommended management strategies within 6 months of diagnosis were also electronically retrieved, including therapy with statins, antiplatelet agents, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and smoking abstention. Main Outcomes and Measures Ankle-brachial index (index ≤0.9 indicates PAD, This population-based cohort study evaluates whether ankle-brachial indices identified through electronic health records among community-dwelling patients with peripheral artery disease are associated with limb revascularization or amputation.

Lower extremity peripheral artery disease (PAD) is highly prevalent. Prognostic risk models supported by automated data extraction of electronic health records (EHRs) would be useful for management of PAD patients. The records-linkage system of the Rochester Epidemiology Project was used to

Klippel-Trenaunay syndrome (KTS) is a complex congenital anomaly featuring two or more of the following: (1) capillary malformations (port-wine stains), (2) soft tissue or bony hypertrophy (or both), and (3) varicose veins or venous malformations. With the purpose of determining the actual significance of venous impairment in patients with KTS, we quantified the venous valvular competency and calf muscle pump function and examined their effect on clinical severity.Included were patients with near-normal function of affected limb(s) and minimal/small foot hypertrophy. Excluded were those with deep venous hypoplasia, aplasia or thrombosis, lymphedema, limb length discrepancy (2.5 cm), peripheral arterial (ankle-brachial index1.0), or cardiac disease and walking impairment. Venous duplex scanning, ascending venography, magnetic resonance imaging, strain gauge plethysmography, and a bone scanogram were performed. We studied eight men and seven women aged 15 to 51 years (median, 24 years). The KTS involved 17 limbs (unilateral in 13 patients and bilateral in 2). Contralateral limbs in patients with unilateral KTS acted as controls (n = 13). Venous clinical severity was graded according to the CEAP and venous clinical severity score (VCSS), and reflux complexity was classified according to the venous segmental disease score. Outflow obstruction (outflow fraction at 1 and 4 seconds; OF(1) and OF(4), respectively), reflux (venous filling index), calf muscle pump function (ejection fraction), and hypertension (residual volume fraction) were determined in both limbs with strain gauge plethysmography. Data, reported as median and interquartile range, were analyzed with the Mann-Whitney test.Varicose veins or venous malformations occurred in the medial, posterior, or anterolateral limb segments of the ankle (7/17, 7/17, and 9/17), calf (10/17, 8/17, and 12/17), knee (9/17, 8/17, and 8/17), and thigh (10/17, 6/17, and 8/17, respectively). Venous malformations occupied the subcutaneous space (17/17) and extended into the subfascial space in 6 (35.3%) of 17 limbs. Abnormal reflux (0.5 seconds) was distributed in the great (64.7%; 11/17) and small (5.9%; 1/17) saphenous veins and the common femoral (23.5%; 4/17), femoral (41.1%; 7/17), popliteal (29.4%; 5/17), perforator (70.6%; 12/17), and axial calf (35.3%; 6/17) veins. There was no difference in the OF(1) and OF(4) between the affected limbs and the controls. Limbs with KTS had a fivefold greater venous filling index (0.133-0.46 mL . 100 mL(-1) . s(-1); 0.258 mL . 100 mL(-1) . s(-1)) than the controls (0.034-0.055 mL . 100 mL(-1) . s(-1); 0.046 mL . 100 mL(-1) . s(-1); P.0001), and this was linked to a higher venous segmental disease score (3 [2-4] vs 0 [0-1]; P.0001). Limbs with KTS had half the ejection fraction (20.8%; 12.3%-24%) of the controls (39.3%; 30.9%-64.6%) and twice as high a residual venous fraction (77% [69.6%-84.5%] vs 40.9% [20.6%-60%]; both P.004). Patients complained of swelling (100%; 15/15), aching (100%; 15/15), pain (93.3%; 14/15) and heaviness (100%; 15/15), tiredness (66.7%; 10/15), and tightness (33.3%; 5/15) of the limb(s) with KTS. Limbs with KTS had a worse (1) venous clinical severity by 11 VCSS points (11 [8-12] vs 0 [0-1]) and (2) clinical status by 3 CEAP classes (C3 [C3-C4] vs C0 [C0-C2]) than the control limbs (both P.0001).Venous disease in limbs with KTS is a major source of morbidity in affected patients. Limbs with KTS are characterized by complex reflux patterns, severe valvular incompetence, calf muscle pump impairment, and venous hypertension, thus explaining the advanced clinical severity (VCSS) and CEAP grade.

International audience; To determine whether postexercise criteria for peripheral artery disease (PAD) diagnosis recommended by the American Heart Association (AHA) identifies the same group of PAD patients.Diagnosis of PAD is performed using ankle-brachial index at rest (resting-ABI). When resting-ABI is not contributive, an AHA scientific statement recommend to use 1 of 2 following criteria: a postexercise ABI decrease of greater than 20% or a postexercise ankle pressure decrease of greater than 30 mm Hg.Between 1996 and 2012, 31,663 consecutive patients underwent lower-extremity arterial study at Mayo Clinic. Among them, only unique patients who had exercise treadmill testing were analyzed. In this retrospective analysis, resting-ABI, postexercise ABI, and postexercise decrease of ankle pressure measured at 1-minute were measured in each patient. We conducted an analysis of agreement between postexercise criteria expressing the agreement separately for the positive and the negative ratings. Twelve thousand three hundred twelve consecutive patients were studied with a mean age of 67 ± 12 years, 61% male. According to resting-ABI, 4317 (35%) patients had PAD. In the whole population, if a clinician diagnoses "PAD" with 1 postexercise criterion, the probability that other clinicians would also diagnose "PAD" is 74.3%. If a clinician diagnoses "no PAD", the probability that other clinicians would also diagnose "no PAD" is 82.4%. In the patients to be of potential benefit from treadmill test when the resting-ABI \textgreater 0.90, if a clinician diagnoses "PAD" with 1 postexercise criterion, the probability that other clinicians would also diagnose "PAD" is 58.4% whereas if a clinician diagnoses "no PAD," the probability that other clinicians would also diagnose "no PAD" is 87.5%.Postexercise criteria do not identify the same group of PAD patients. In our opinion, postexercise criteria to define PAD deserve additional study

Proximal claudication is secondary to ischemia caused by peripheral artery disease (PAD), whereas proximal pseudo-claudication is secondary to other disease processes such as hip arthritis, spinal stenosis, neuropathy, and so forth. The differentiation between the two can be challenging. Exercise transcutaneous oxygen pressure measurement (exercise-TcPO2) allows noninvasive detection of flow-reducing lesions in the proximal arteries and tributaries of the lower extremity arterial tree. We present the first case report in the United States using an exercise-TcPO2 algorithm. A 71-year-old diabetic patient with proximal left-sided and right-calf claudication with indeterminate ankle-brachial indices underwent an exercise-TcPO2 study before and after endovascular intervention. Four TcPO2 probes were placed: one at chest level (reference probe), one on each buttock, and one on the symptomatic calf. The Delta from Resting Oxygen Pressure (DROP) index was calculated at each probe site using a previously validated protocol. Proximal left- and right-calf ischemia were confirmed by the initial exercise-TcPO2, and, after endovascular treatment of the left iliac artery lesion, improvements in proximal exercise-TcPO2 values were found. These data suggest that exercise-TcPO2 can be useful in PAD evaluation in patients with non-compressible arteries and/or proximal claudication.

Background —Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2 isoforms (ECE-1α and ECE-1β), the result of alternative splicing of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides mediate antiproliferative and vasodilating actions. We sought to demonstrate the distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with atheroma formation. Our hypothesis was that chronic NEP-I, in association with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and associated atheroma formation. Methods and Results —Cholesterol-fed New Zealand White rabbits (n=8, 1% cholesterol diet) and NEP-I–treated cholesterol-fed New Zealand White rabbits (n=8; candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1α and ECE-1β immunoreactivity was present in the aortas of both groups. Compared with control values, plasma cGMP concentrations were increased (2.8±0.6 versus 8.4±1.2 pmol/mL, P P P P Conclusions —These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.

OBJECTIVES We sought to define the vascular actions of the cardiac hormone brain natriuretic peptide (BNP) on cellular proliferation and cyclic guanosine monophosphate (cGMP) in human aortic vascular smooth muscle cells (HAVSMCs). Secondly, we investigated BNP and acetylcholine (ACh) vasorelaxations in aortic rings from normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of neutral endopeptidase (NEP). BACKGROUND The vascular actions of BNP are not well defined, despite the presence of its receptor in vascular smooth muscle and the upregulation of NEP, the ectoenzyme that degrades BNP, in the vascular wall in atherosclerosis. METHODS HAVSMCs stimulated with fetal calf serum (FCS) were pulsed with bromodeoxyuridine (BrdU) with and without BNP. The HAVSMCs were incubated in the presence and absence of BNP to assess cGMP. Vasorelaxations to BNP and ACh were assessed in rings in normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of NEP, together with assessment of atheroma formation. RESULTS FCS-stimulated BrdU uptake in HAVSMCs was suppressed with BNP. BNP potentiated cGMP in HAVSMCs. BNP resulted in potent vasorelaxation in normal isolated aortic rings, which were impaired in atherosclerotic versus normal rabbits and preserved with NEP inhibition, which also decreased atheroma formation. Relaxations to ACh, which were also impaired in atherosclerosis, were preserved with inhibition of NEP. CONCLUSIONS We conclude that BNP potently inhibits vascular smooth muscle cell proliferation and potentiates the generation of cGMP. BNP potently relaxes the normal rabbit aorta, and this response is impaired in atherosclerosis but preserved with inhibition of NEP, together with a reduction in atheroma formation and preservation of relaxations to ACh.

Nitric oxide (NO) is an important endothelium-derived relaxing factor that functions via activation of soluble guanylyl cyclase and cGMP generation in vascular smooth muscle. Recently, studies have described the synthesis and secretion of C-type natriuretic peptide (CNP) from endothelial cells. This peptide also mediates relaxation via cGMP but through activation of particulate guanylyl cyclase. We tested the hypothesis that endothelium-dependent relaxations to acetylcholine or bradykinin in isolated canine coronary arteries involve both releases of NO and CNP. Rings of canine coronary arteries were incubated with either inhibitors of NO production ( NG-monomethyl-l-arginine,l-NMMA) or the natriuretic peptide receptor antagonist HS-142-1. CNP caused concentration-dependent relaxations of rings with and without endothelium. These relaxations were attenuated by HS-142-1. Relaxations to acetylcholine and bradykinin were attenuated byl-NMMA alone but not attenuated by HS-142-1 alone. Coinhibition withl-NMMA and HS-142-1 significantly inhibited acetylcholine- and bradykinin-induced relaxation to a magnitude greater than either inhibitor alone. In summary, a novel interaction between the NO and the natriuretic peptide system is demonstrated by increased attenuation of endothelium-dependent relaxations to acetylcholine and bradykinin when both NO synthase and natriuretic peptide receptors are inhibited. These investigations support the concept of release of multiple endothelium-derived factors in response to acetylcholine- and bradykinin-receptor stimulation in endothelial cells, which may include CNP, as well as NO.

Objective To determine whether Dendroaspis natriuretic peptide (DNP), a novel peptide isolated from the venom of the Dendroaspis angusticeps snake that contains a 17-amino acid disulfide ring structure similar to that in atrial, brain, and C-type natriuretic peptides, is present in normal human plasma and myocardium and whether, like the other natriuretic peptides, DNP-Iike immunoreactivity (DNP-LI) is activated in human congestive heart failure (CHF). Material and Methods Circulating DNP-LI was assessed in 19 normal human subjects and 19 patients with CHF (New York Heart Association class III or IV) with a specific and sensitive radioimmunoassay for DNP with no cross-reactivity with the other natriuretic peptides. Immunohistochemical studies that used polyclonal rabbit anti-DNP antiserum were performed on human atrial myocardial tissue obtained from four patients with endstage CHF who were undergoing cardiac transplantation and from three donor hearts at the time of transplantation. Results We report that DNP-LI circulates in normal human plasma and is present in the normal atrial myocardium. In addition, DNP-LI is increased in the plasma of patients with CHF. Conclusion This study demonstrates, for the first time, the presence of a DNP-like peptide in normal human plasma and in the atrial myocardium. Additionally, these studies demonstrate increased plasma DNP-LI in human CHF. These results support the possible existence of an additional new natriuretic peptide in humans, which may have a role in the neurohumoral activation that characterizes human CHF.